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The epidermal growth factor receptor (EGFR) functions as a central signaling hub that integrates biochemical and mechanical cues essential for tissue development, homeostasis, and disease. Emerging evidence highlights how EGFR activity is finely regulated through its spatial organization at the plasma membrane, intracellular trafficking pathways, and interactions with organelles via specialized membrane contact sites. In addition to its well-established ligand-dependent activation, EGFR also mediates ligand- and kinase-independent functions, adding further complexity to its roles in physiology and pathology, particularly in cancer. This review explores how ligand diversity, cellular context, and mechanical stimuli converge to shape EGFR signaling, emphasizing the integration of ligand-dependent and -independent mechanisms in determining cellular outcomes. We also discuss how these emerging functions influence cancer cell metabolism and survival. A deeper understanding of these intricate signaling networks may inform the development of novel therapeutic strategies to modulate EGFR activity in cancer.

The integration of endocytic routes is critical to regulate receptor signaling. A nonclathrin endocytic (NCE) pathway of the epidermal growth factor receptor (EGFR) is activated at high ligand concentrations and targets receptors to degradation, attenuating signaling. Here we performed an unbiased molecular characterization of EGFR-NCE.We identified NCE-specific regulators, including the endoplasmic reticulum (ER)–resident protein reticulon 3 (RTN3) and a specific cargo, CD147. RTN3 was critical for EGFR/CD147-NCE, promoting the creation of plasma membrane (PM)–ER contact sites that were required for the formation and/or maturation of NCE invaginations. Ca2+ release at these sites, triggered by inositol 1,4,5-trisphosphate (IP₃)–dependent activation of ER Ca2+ channels, was needed for the completion of EGFR internalization. Thus, we identified a mechanism of EGFR endocytosis that relies on ER-PM contact sites and local Ca2+ signaling.

The cancer therapeutic cetuximab blocks EGFR signaling on tumor cells. Pozzi et al . now show that this antibody, when combined with chemotherapy, can also kill colorectal cancer cells by triggering immunogenic cell death. Cetuximab is a monoclonal antibody that is effective in the treatment of metastatic colorectal cancer (mCRC). Cetuximab blocks epidermal growth factor receptor (EGFR)-ligand interaction and inhibits downstream RAS–ERK activation. However, only some activating mutations in RAS affect cetuximab efficacy, and it is not clear what else mediates treatment success. Here we hypothesized that cetuximab induces immunogenic cell death (ICD) that activates a potent antitumor response. We found that cetuximab, in combination with chemotherapy, fostered ICD in CRC cells, which we measured via the endoplasmic reticulum (ER) stress response and an increase in phagocytosis by dendritic cells. ICD induction depended on the mutational status of the EGFR signaling pathway and on the inhibition of the splicing of X-box binding protein 1 ( XBP1 ), an unfolded protein response (UPR) mediator. We confirmed the enhanced immunogenicity elicited by cetuximab in a mouse model of human EGFR-expressing CRC. Overall, we demonstrate a new, immune-related mechanism of action of cetuximab that may help to tailor personalized medicine.

Ubiquitination of the epidermal growth factor receptor (EGFR) that occurs when Cbl and Grb2 bind to three phosphotyrosine residues (pY1045, pY1068 and pY1086) on the receptor displays a sharp threshold effect as a function of EGF concentration. Here we use a simple modelling approach together with experiments to show that the establishment of the threshold requires both the multiplicity of binding sites and cooperative binding of Cbl and Grb2 to the EGFR. While the threshold is remarkably robust, a more sophisticated model predicted that it could be modulated as a function of EGFR levels on the cell surface. We confirmed experimentally that the system has evolved to perform optimally at physiological levels of EGFR. As a consequence, this system displays an intrinsic weakness that causes—at the supraphysiological levels of receptor and/or ligand associated with cancer—uncoupling of the mechanisms leading to signalling through phosphorylation and attenuation through ubiquitination. Cells respond to increasing concentrations of EGF by altering the balance between EGFR phosphorylation and ubiquitination. Here the authors show that the establishment of an EGFR signaling threshold requires both a multiplicity of binding sites and cooperative binding of Cbl and Grb2 to the EGFR.

How the cell converts graded signals into threshold‐activated responses is a question of great biological relevance. Here, we uncover a nonlinear modality of epidermal growth factor receptor (EGFR)‐activated signal transduction, by demonstrating that the ubiquitination of the EGFR at the PM is threshold controlled. The ubiquitination threshold is mechanistically determined by the cooperative recruitment of the E3 ligase Cbl, in complex with Grb2, to the EGFR. This, in turn, is dependent on the simultaneous presence of two phosphotyrosines, pY1045 and either one of pY1068 or pY1086, on the same EGFR moiety. The dose–response curve of EGFR ubiquitination correlate precisely with the non‐clathrin endocytosis (NCE) mode of EGFR internalization. Finally, EGFR‐NCE mechanistically depends on EGFR ubiquitination, as the two events can be simultaneously re‐engineered on a phosphorylation/ubiquitination‐incompetent EGFR backbone. Since NCE controls the degradation of the EGFR, our findings have implications for how the cell responds to increasing levels of EGFR signalling, by varying the balance of receptor signalling and degradation/attenuation. The amount of EGF present for binding to its receptor governs an on–off switch of EGFR ubiquitination and hence ligand‐controlled non‐clathrin‐mediated endocytosis and EGFR degradation.

The integration of endocytic routes is critical to regulate receptor signaling. A non-clathrin endocytic pathway (NCE) of the epidermal growth factor receptor (EGFR) is activated at high ligand concentrations and targets receptors to degradation, attenuating signaling. Here we performed an unbiased molecular characterization of EGFR-NCE. We identified NCE-specific regulators, including the endoplasmic reticulum (ER)-resident protein reticulon-3 (RTN3), and a specific cargo, CD147. RTN3 was critical for EGFR/CD147-NCE, promoting the creation of plasma membrane (PM)–ER contact sites that were required for the formation/maturation of NCE invaginations. Ca2+ release at these sites, triggered by IP3-dependent activation of ER Ca2+ channels, was needed for the completion of EGFR internalization. Thus, we identified a mechanism of EGFR endocytosis that relies on ER-PM contact sites and local Ca2+ signaling.

Objectives Computed tomography (CT) provides excellent anatomy assessment of the aortic annulus (AoA) and is utilized for pre-procedural planning of transcatheter aortic valve implantation (TAVI). We sought to investigate if geometrical characteristics of the AoA determined by CT may represent predictors of structural valve degeneration (SVD) in patients undergoing TAVI with balloon-expandable valves. Methods This is a retrospective study on 124 consecutive patients (mean age: 79 ± 7 years; female: 61%) undergoing balloon-expandable TAVI prospectively enrolled in a registry . AoA maximum diameter ( D max ), minimum diameter ( D min ), and area were assessed using pre-procedural CT. SVD was identified during follow-up with transthoracic echocardiography documenting structural prosthetic valve abnormalities with or without hemodynamic changes. Results The mean follow-up was 5.9 ± 1.7 years. SVD was found in 48 out of 124 patients (38%). AoA D max , D min , and area were significantly smaller in patients with SVD compared to patients without SVD (25.6 ± 2.2 mm vs. 27.1 ± 2.8 mm, p = 0.012; 20.5 ± 2.1 mm vs. 21.8 ± 2.1 mm, p = 0.001 and 419 ± 77 mm 2 vs. 467 ± 88 mm 2 , p = 0.002, respectively). At univariable analysis, female sex, BSA, 23-mm prosthetic valve size, D max < 27.1 mm, and a D min < 19.9 mm were associated with SVD, whereas at multivariable analysis, only D min < 19.9 mm (OR = 2.873, 95% CI: 1.191–6.929, p = 0.019) and female sex (OR = 2.659, 95% CI: 1.095–6.458, p = 0.031) were independent predictors of SVD. Conclusions Female sex and AoA D min < 19.9 mm are associated with SVD in patients undergoing TAVI with balloon-expandable valves. When implanting large prostheses in order to avoid paraprosthetic regurgitation, caution should be observed due to the risk of excessive stretching of the AoA D min, which may play a role in SVD. Key Points • Long-term durability is a concern for transcatheter aortic valve bioprosthesis. • CT provides an excellent assessment of the aortic annulus’s geometrical characteristics for prosthesis sizing before transcatheter aortic valve implantation (TAVI). • Female sex and a small minimum aortic annulus diameter measured with CT are independent predictors of structural valve degeneration in patients undergoing TAVI with balloon-expandable valves.

Hypertrophic cardiomyopathy (HCM) primarily affects the left ventricle (LV) sparing the right ventricle (RV) in vast majority of cases. However, several studies employing CMR have revealed that myocardial hypertrophy may also involve the RV. To assess RV size and function in a large prospectively cohort of HCM patients and to evaluate whether these parameters in association with other MR findings can predict cardiac events. Two participating centers prospectively included patients with known or suspected HCM between 2011 and 2017. CMR studies were performed with three different scanners. Outcome measures were a composite of ventricular arrhythmias, hospitalization for HF and cardiac death. Of 607 consecutive patients with known or suspected HCM, 315 had complete follow-up information (mean 65 ± 20 months). Among them, 115 patients developed major cardiac events (MACE) during follow-up. At CMR evaluation, patients with events had higher left atrium (LA) diameter (41.5 ± 8 mm vs. 37.17 ± 7.6 mm, p < 0.0001), LV mass (156.7 vs. 144 g, p = 0.005) and myocardial LGE (4.3% vs. 1.9%, p = 0.001). Similarly, patients with events had lower RV stroke volume index (42.7 vs. 47.0, p = 0.0003) and higher prevalence of both RV hypertrophy (16.4% vs. 4.7%, p = 0.0005) and reduced RV ejection fraction (12.2% vs. 4.4%, p = 0.006). In the multivariate analysis, LA diameter and RV stroke volume index were the strongest predictors of events (p < 0.001 and p = 0.0006, respectively). Anatomic and functional RV anomalies detected and characterized with CMR may have may have a major role in predicting the prognosis of HCM patients.